A5069401956- Bladder and Urothelial Cancer Treatments
- Cancer Immunotherapy and Biomarkers
- Advanced Breast Cancer Therapies
- Cancer Treatment and Pharmacology
- Estrogen and related hormone effects
- Cancer Genomics and Diagnostics
- Urinary and Genital Oncology Studies
- PI3K/AKT/mTOR signaling in cancer
- Renal cell carcinoma treatment
- HER2/EGFR in Cancer Research
- Inflammatory mediators and NSAID effects
- Lung Cancer Research Studies
- Lung Cancer Treatments and Mutations
- Pancreatic and Hepatic Oncology Research
- Ferroptosis and cancer prognosis
- Cancer, Stress, Anesthesia, and Immune Response
- Pancreatitis Pathology and Treatment
- Economic and Financial Impacts of Cancer
- Renal and related cancers
- PARP inhibition in cancer therapy
- Heat shock proteins research
- Breast Cancer Treatment Studies
- Colorectal Cancer Treatments and Studies
- Protein Degradation and Inhibitors
- Cancer Research and Treatments
Queen Mary University of London
2015-2023
Imperial College London
2013-2021
St Bartholomew's Hospital
2021
Barts Health NHS Trust
2016-2020
Breast Cancer Now
2019
Guy's and St Thomas' NHS Foundation Trust
2018-2019
King's College Hospital NHS Foundation Trust
2019
Royal Cornwall Hospital
2016-2019
Institute of Cancer Research
2018
Ontario Institute for Cancer Research
2018
PURPOSE The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently activated in triple-negative breast cancer (TNBC). AKT inhibitor capivasertib has shown preclinical activity TNBC models, and drug sensitivity been associated with activation of PI3K or and/or deletions PTEN. PAKT trial was designed to evaluate the safety efficacy adding paclitaxel as first-line therapy for TNBC. PATIENTS AND METHODS This double-blind, placebo-controlled, randomized phase II recruited women...
Abstract Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms stroma to suppress ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients advanced, unresectable PDAC (n = 27), ATRA is re-purposed as stromal-targeting agent combination gemcitabine-nab-paclitaxel chemotherapy using two-step adaptive continual re-assessment method design. The maximum tolerated (MTD) recommended 2...
Metastatic papillary renal cancer (PRC) has poor outcomes, and new treatments are required. There is a strong rationale for investigating mesenchymal epithelial transition receptor (MET) programmed cell death ligand-1 (PD-L1) inhibition in this disease. In study, the combination of savolitinib (MET inhibitor) durvalumab (PD-L1 investigated.This single-arm phase II trial explored (1,500 mg once every four weeks) (600 daily; ClinicalTrials.gov identifier: NCT02819596). Treatment-naïve or...
4506 Background: Atezolizumab is a PD-L1 inhibitor which licenced in metastatic urothelial cancer. This study investigates the efficacy and safety of neoadjuvant atezolizumab given prior to cystectomy operable muscle invasive transitional cell carcinoma bladder Methods: single arm phase 2 investigated cycles (1200mg Q3) cancer (T2-4N0M0). Pathological complete response (pCR) occurring ≥20% patients was primary endpoint. Biomarker analysis on sequential tissue co-primary Cross sectional...
Randomized clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mammalian target rapamycin complex 1 (mTORC1) but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, dual inhibitor mTORC1 and has broad activity in preclinical breast cancer models, showing superior everolimus.
1007 Background: The PI3K/AKT signalling pathway is frequently activated in triple-negative breast cancer (TNBC). AZD5363 a highly-selective, oral, small molecule AKT inhibitor. PAKT trial investigated the addition of to paclitaxel as 1st-line therapy for TNBC. Methods: This investigator-led, double-blind, placebo-controlled, randomised phase II trial, recruited women with previously untreated, metastatic TNBC at 42 sites 6 countries. Patients were randomly assigned (1:1) 90mg/m2 (days 1, 8,...
545 Background: Metastatic papillary renal cancer (PRC) has poor outcomes and there is need for new treatments. There a strong rationale investigating MET PD-L1 inhibition in this disease. In study, we investigate savolitinib (MET inhibitor) durvalumab (PD-L1 together. Methods: This single arm phase I/II trial explored at starting doses of 1500mg Q4W 600mg OD respectively, with 4wk run-in. Treatment naïve or previously treated patients metastatic PRC were included. Response rate (RR) (RECIST...
<h3>Importance</h3> Patients with breast cancer remain at risk of relapse after adjuvant therapy. Celecoxib has shown antitumor effects in preclinical models human cancer, but clinical evidence is lacking. <h3>Objective</h3> To evaluate the role celecoxib as an addition to conventional therapy for women ERBB2 (formerly HER2)–negative primary cancer. <h3>Design, Setting, and Participants</h3> The Randomized European Trial (REACT) was a phase 3, randomized, double-blind study conducted 160...
619 Background: There is a strong rationale for investigating MET and PD-L1 inhibition in metastatic papillary renal cancer (PRC). We previously reported response rates (RR) progression free survival (PFS) savolitinib (MET inhibitor) durvalumab (PD-L1 together. Here we report overall (OS) data available 12 months after the last patient was enrolled. Methods: This single arm phase I/II trial explores (1500mg Q4W) (600mg OD) together PRC, with 4wk run in. Treatment naïve or treated patients...
4511 Background: Savolitinib is a potent and selective MET inhibitor with activity in MET-driven papillary renal cancer (PRC). Durvalumab PD-L1 which has been tested combination savolitinib metastatic PRC response rates of 29% (12/41). Here we describe the efficacy this PRC. Methods: This single arm phase I/II trial explored durvalumab (1500mg Q4W) (600mg OD) together PRC, 4wk run in. Biomarker analysis results were compared responses to treatment as planned protocol. The presented here...
2548 Background: PI3K/mTOR and MAPK pathways are aberrantly activated in many tumours interact to promote tumour growth therapeutic resistance. Activity of single pathway inhibition is limited due compensatory activation alternative signalling pathways. Dual has demonstrated synergistic activity preclinical models, with broad across a range molecular backgrounds. This study was designed evaluate the optimal doses schedule vistusertib (dual mTOR1/2 inhibitor) selumetinib (MEK1/2 when given...
Abstract Background: Resistance to endocrine therapy remains a major clinical challenge in ER+ breast cancer. Aberrant PI3K/AKT/mTOR pathway activation frequently occurs cancer and is associated with resistance therapy. Randomised trials have demonstrated substantial benefit of adding everolimus treatment. However, there increasing evidence that inhibition only mTORC1 rapalogues such as sets off negative feedback mechanism leads increased AKT signalling linked treatment resistance. AZD2014...
Abstract Background: Resistance to endocrine therapy remains a major clinical challenge with aberrant PI3K/ mTOR pathway activation being one of the main drivers. Randomised trials have demonstrated substantial benefit adding everolimus therapy. Vistusertib (AZD2014), dual inhibitor mTORC1 and mTORC2, has shown broader range activity in preclinical ER+ breast cancer models, showing superior (EVE) both hormone-sensitive resistant models. The MANTA trial was desgined evaluate safety efficacy...
Abstract Background Inhibition of COX-2 has been shown to attenuate the metastatic process in pre-clinical models human breast cancer (BC). The primary aim this study was assess effect 2 years adjuvant therapy with inhibitor celecoxib compared placebo HER2-ve BC patients. Patients & Methods were randomised a 2:1 ratio receive 400mg once daily or for years. had have completely resected prior local and systemic treatment according practice. Concurrent radiotherapy permitted hormone...
TPS115 Background: Celecoxib is a selective COX-2 inhibitor licensed for the treatment of chronic arthritis. However, an association between non-steroidal anti-inflammatory drug (NSAID) use and decreased breast cancer risk in women has also been demonstrated (Harris et al, Epidemiology, 1996), believed to be due inhibition enzyme. Preclinical data shown that inhibitors can prevent mammary tumour formation Can Res, 2000), inhibit angiogenesis (Rozic Int J Cancer, 2001) reverse resistance...
Abstract Background: In the PAKT study, addition of oral AKT inhibitor capivasertib to 1st-line paclitaxel therapy for metastatic TNBC resulted in significantly longer progression-free survival (PFS; primary endpoint; Schmid, J Clin Oncol 2020). The stratified PFS hazard ratio was 0.74 (95% CI, 0.50-1.08; one-sided P=0.06; predefined significance level 0.10, one-sided; median 5.9 vs 4.2 months with placebo). Overall (OS) results were immature at analysis 53% events but suggested long OS (HR,...
Abstract Management of metastatic TNBC remains a challenge. Chemotherapy is the mainstay treatment but benefits are frequently short-lived with rapid development resistance. The PI3K/AKT/mTOR pathway has been implicated in many ways TNBC, making inhibition AKT an attractive therapeutic target. Based on downstream activation signatures, PI3K appears higher compared to other molecular subtypes, despite relatively low percentage activating mutations. Alternative means have identified including...